Modulation of Serotonin 2C Receptor Editing by Sustained Changes in Serotonergic Neurotransmission

Abstract

Serotonin 2C (5-HT 2C ) receptor pre-mRNA is a substrate for RNA editing enzymes that convert five adenosines (named A, B, CЈ, C, and D editing sites) to inosines. Editing of two of these sites (CЈ and C) is crucial for decreasing the efficiency of the receptor to activate G-protein. Nucleotide sequence analysis of mouse forebrain neocortical 5-HT 2C mRNA isoforms revealed that editing at these two sites is regulated in a serotonindependent manner. In serotonin-depleted mice, CЈ-and C-site editing is significantly decreased. This results in an increased expression of 5-HT 2C mRNA isoforms encoding receptors with higher sensitivity to serotonin. In contrast, a 4 d treatment with the 5-HT 2A/2C agonist (Ϯ)-1-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane significantly increases the editing frequency at the CЈ site and leads to increased expression of 5-HT 2C mRNA isoforms encoding receptors that activate G-protein least efficiently. None of the drug treatments led to alterations in cytoplasmic 5-HT 2C mRNA levels. These data indicate that editing of 5-HT 2C pre-mRNA is a mechanism that retains basic response properties of 5-HT 2C receptors in the face of changing synaptic input to keep receptor activation within an optimal range for information processing. Key words: serotonin; 5-HT 2C receptor; RNA editing; forebrain neocortex; 5-HT depletion; 5-HT 2A/2C agonistThe conversion of adenosine (A) to inosine (I) by ADARs (adenosine deaminases that act on RNA) is the most widespread editing in higher eukaryotes (Bass, 2002). Although the total inosine content of rat brain poly(A ϩ ) RNA predicts that one inosine occurs approximately once every 17,000 nucleotides (Paul and Bass, 1998), only a few neuronal substrates for A to I editing have been identified. They include the serotonin 2C (5-HT 2C ) receptor, the first G-protein-coupled receptor known to be edited. In 5-HT 2C pre-mRNA, a total of five closely spaced adenosines (named A, B, CЈ, C, and D editing sites) located within a sequence that encodes the second intracellular loop of the receptors protein can be converted to inosines (Burns et al., 1997;Niswender et al., 1999). This editing can change up to three triplet codons and has the potential to generate 24 different protein isoforms. Compared with nonedited 5-HT 2C receptors, the receptor isoform that results from editing at the ABCD sites and other partially edited isoforms that are edited at the CЈsite but not the C site exhibit a fourfold reduction in the efficiency to activate G-protein in response to agonist stimulation. This reduction is even higher (15-to 25-fold) for completely edited isoforms and other partially edited isoforms that are edited at both CЈ and C sites. Other partially edited isoforms that are not edited at the CЈ and/or C site appear to be fully functional (Niswender et al., 1999;Wang et al., 2000).At present, the significance of 5-HT 2C pre-mRNA editing in vivo is still unknown. However, a recent study indicates that this editing is regulated and suggests that this regulation is sensitive ...

Differential Regulation of the Mesoaccumbens Dopamine Circuit by Serotonin2C Receptors in the Ventral Tegmental Area and the Nucleus Accumbens: An In Vivo Microdialysis Study with Cocaine

“…In this context, it is noteworthy that 5-HT 2C Rs undergo a region-dependent RNA editing (Burns et al, 1997), a mechanism that generates distinct functional populations of 5-HT 2C Rs with different levels of constitutive activity Navailles et al, 2006b) and different desensitization rate (Marion et al, 2004). Specifically, the pattern of 5-HT 2C R edited isoforms may determine the response to endogenous 5-HT (Herrick-Davis et al, 1999) and control the signal-tonoise ratio at central 5-HT synapses (Gurevich et al, 2002;Niswender et al, 1999). In the NAc, 5-HT 2C R, transcripts are densely expressed in the anterior compartment and appear to localize to medium-sized neurons that express the distribution, localization, and morphology typical of striatal GABA efferent neurons (Eberle-Wang et al, 1997;Morilak et al, 1993).…”

Increased serotonin 2C receptor mRNA editing: a possible risk factor for suicide

“…42 Specifically, the frequencies of less edited or unedited isoforms with higher sensitivity to serotonin were increased when serotonin was depleted by as much as 80%. Conversely, a serotonin agonist increased the frequency of more edited isoforms that activate G-protein coupling less efficiently.…”

“…47 Because increased 5-HT 2C R editing can hamper the responsivity of this receptor subtype to serotonin, our findings suggest that antidepressant therapies, especially those that involve serotonin reuptake inhibition, may be less effective in blunting suicidal tendencies in a subpopulation of patients with an inherently high level of the VSV isoform. Moreover, the proportion of the VSV isoform could be additionally enhanced in these individuals during the initial stages of SSRI therapy as an adaptation to the augmented levels of serotonin in the synapse 22,42 contributing to suicidality in this vulnerable subgroup of patients.…”

Editing of the serotonin 2C receptor pre-mRNA: Effects of the Morris Water Maze

“…Abnormalities in patterns of HTR2C editing have been reported in subsets of patients with schizophrenia and depression (Gurevich et al 2002a;Niswender et al 2001;Dracheva et al 2003), and baseline differences have also been reported among different inbred mouse strains (Englander et al 2005;Hackler et al 2006;Du et al 2006). Changes in editing patterns have been induced, in rodents, by exposure to tests of anxiety, including the forced swim test and learned helplessness, and by drugs, such as fluoxetine (Gurevich et al 2002b;Iwamoto et al 2005;Englander et al 2005;Yang et al 2004). Most of the changes in editing patterns induced by disease, genetic background, stress and pharmacological treatment are subtle and the corresponding diversity at the protein level has not yet been studied.…”